Stages Of Alcohol Use Disorder Research Articles

The Role of Unawareness, Volition, and Neural Hyperconnectivity in Alcohol Use Disorder: A Functional Magnetic Resonance Imaging Study

BackgroundAutomated alcohol craving and habitual alcohol consumption characterize the later stages of alcohol use disorder (AUD). This study reanalyzed previously collected functional neuroimaging data in combination with the Craving Automated Scale for Alcohol (CAS-A) questionnaire to investigate the neural correlates and brain networks underlying automated drinking characterized by unawareness and nonvolition. MethodsWe assessed 49 abstinent male patients with AUD and 36 male healthy control participants during a functional magnetic resonance imaging–based alcohol cue–reactivity task. We performed whole-brain analyses examining the associations between CAS-A scores and other clinical instruments and neural activation patterns in the alcohol versus neutral contrast. Furthermore, we performed psychophysiological interaction analyses to assess the functional connectivity between predefined seed regions and other brain areas. ResultsIn patients with AUD, higher CAS-A scores correlated with greater activation in dorsal striatal, pallidal, and prefrontal regions, including frontal white matter, and with lower activation in visual and motor processing regions. Between-group psychophysiological interaction analyses showed extensive connectivity between the seed regions inferior frontal gyrus and angular gyrus and several frontal, parietal, and temporal brain regions in AUD versus healthy control participants. ConclusionsThe present study applied a new lens to previously acquired alcohol cue–reactivity functional magnetic resonance imaging data by correlating neural activation patterns with clinical CAS-A scores to elucidate potential neural correlates of automated alcohol craving and habitual alcohol consumption. Our results support previous findings showing that alcohol addiction is associated with hyperactivation in habit-processing regions, with hypoactivation in areas mediating motor and attention processing, and with general hyperconnectivity.

Neural cue reactivity is not stronger in male than in female patients with alcohol use disorder.

Males consume more alcohol than females, and alcohol use disorder (AUD) is more prevalent in males than females. However, females progress faster to AUD. Sex differences in neural alcohol cue reactivity were previously observed in young social drinkers, indicating a role of hypersensitivity to alcohol-related cues in very early stages of addiction. To our knowledge, this is the first study on patients diagnosed with AUD to test sex differences in neural reactivity to alcohol cues in order to widen previous findings. We analyzed data from previous studies, using a well-established functional magnetic resonance imaging (fMRI) paradigm to compare neural reactivity to alcohol cues between 42 female and 124 male patients with AUD (mean age 45 and 46 years) in predefined regions of interest that were implicated by previous studies (ventral and dorsal striatum as well as caudate, putamen, amygdala, hippocampus, insula, anterior cingulate cortex, and medial prefrontal cortex) using independent samples t-tests. Post-hoc, effect size calculations were performed. Throughout all nine regions of interest, we found no statistically significant sex differences in neural reactivity toward alcoholic pictures alone or in comparison to neutral pictures (p > 0.05, FDR-corrected). Post-hoc effect size estimates indicated a magnitude between 0.137 and 0.418 (Hedge's g) on alcohol reactivity to alcohol cues compared to neutral cues and indicate very small to less than medium effect sizes in the direction of higher cue reactivity in female patients. Previous studies showed sex differences in neural alcohol cue reactivity in younger social and problematic alcohol drinkers, i.e., stronger striatal cue-reactivity in males. After correction for multiple comparisons, we did not observe significant sex differences in a cohort of middle-aged females and males with AUD. Sex differences that are present during early phases of addiction development might disappear at later stages of AUD and might thus be considered as clinically less relevant in patients with more severe AUD.

Pituitary adenylate cyclase-activating polypeptide (PACAP) modulates dependence-induced alcohol drinking and anxiety-like behavior in male rats

Alcohol use disorder (AUD) is a devastating illness defined by periods of heavy drinking and withdrawal, often leading to a chronic relapsing course. Initially, alcohol is consumed for its positive reinforcing effects, but later stages of AUD are characterized by drinking to alleviate withdrawal-induced negative emotional states. Brain stress response systems in the extended amygdala are recruited by excessive alcohol intake, sensitized by repeated withdrawal, and contribute to the development of addiction. In this study, we investigated one such brain stress response system, pituitary adenylate cyclase-activating polypeptide (PACAP), and its cognate receptor, PAC1R, in alcohol withdrawal-induced behaviors. During acute withdrawal, rats exposed to chronic intermittent ethanol vapor (ethanol-dependent) displayed a significant increase in PACAP levels in the bed nucleus of the stria terminalis (BNST), a brain area within the extended amygdala critically involved in both stress and withdrawal. No changes in PACAP levels were observed in the central nucleus of the amygdala. Site-specific microinfusion of the PAC1R antagonist PACAP(6-38) into the BNST dose-dependently blocked excessive alcohol intake in ethanol-dependent rats without affecting water intake overall or basal ethanol intake in control, nondependent rats. Intra-BNST PACAP(6-38) also reversed ethanol withdrawal-induced anxiety-like behavior in ethanol-dependent rats, but did not affect this measure in control rats. Our findings show that chronic intermittent exposure to ethanol recruits the PACAP/PAC1R system of the BNST and that these neuroadaptations mediate the heightened alcohol drinking and anxiety-like behavior observed during withdrawal, suggesting that this system represents a major brain stress element responsible for the negative reinforcement associated with the "dark side" of alcohol addiction.

From Pleasure to Pain, and Back Again: The Intricate Relationship Between Alcohol and Nociception.

A close and bidirectional relationship between alcohol consumption and pain has been previously reported and discussed in influential reviews. The goal of the present narrative review is to provide an update on the developments in this field in order to guide future research objectives. We evaluated both epidemiological and neurobiological literature interrogating the relationship between alcohol use and pain for the presence of significant effects. We outlined studies on interactions between alcohol use and pain using both self-reports and objective experimental measures and discussed potential underlying mechanisms of these interactions. Epidemiological, preclinical and clinical literature point to three major interactions between alcohol use and pain: (a) alcohol use leading to hyperalgesia, (b) alcohol use moderating pain and hyperalgesia and (c) chronic pain as a risk factor predisposing to alcohol relapse. Neurobiological studies using animal models to assess these interactions have transitioned from mostly involuntary modes of experimenter-controlled alcohol administration to self-administration procedures, and increasingly indicate that neuronal circuits implicated in both withdrawal and anticipation stages of alcohol use disorder also have a role in chronic pain. Mechanistically, alterations in GABA, glutamate, the corticotropin-releasing factor system, endogenous opioids and protein kinase C appear to play crucial roles in this maladaptive overlap. Many of the principles explaining the interactions between alcohol and pain remain on a strong foundation, but continuing progress in modeling these interactions and underlying systems will provide a clearer basis for understanding, and ultimately treating, the damaging aspects of this interaction.

Emerging Role of Epigenetic Mechanisms in Alcohol Addiction.

Alcohol use disorder (AUD) is a complex brain disorder with an array of persistent behavioral and neurochemical manifestations. Both genetic and environmental factors are known to contribute to the development of AUD, and recent studies on alcohol exposure and subsequent changes in gene expression suggest the importance of epigenetic mechanisms. In particular, histone modifications and DNA methylation have emerged as important regulators of gene expression and associated phenotypes of AUD. Given the therapeutic potential of epigenetic targets, this review aims to summarize the role of epigenetic regulation in our current understanding of AUD by evaluating known epigenetic signatures of brain regions critical to addictive behaviors in both animal and human studies throughout various stages of AUD. More specifically, the effects of acute and chronic alcohol exposure, tolerance, and postexposure withdrawal on epigenetically induced changes to gene expression and synaptic plasticity within key brain regions and the associated behavioral phenotypes have been discussed. Understanding the contribution of epigenetic regulation to crucial signaling pathways may prove vital for future development of novel biomarkers and treatment agents in ameliorating or preventing AUD.